Dutch study finds Gene that paves way for treatment of potentially fatal vascular complications in people with diabetes

An Australian-Dutch research team led by Prof Harald Schmidt from Maastricht University and Prof Karin Jandeleit-Dahm from the Baker IDI Heart & Diabetes Institute in Melbourne, has confirmed the role of a specific enzyme in the accelerated development of diabetic atherosclerosis. By suppressing the gene coding for this enzyme or inhibiting the activity of the enzyme, researchers were able to significantly reduce damage such as inflammation and fibrosis, paving the way for a new approach to prevention and treatment of cardiovascular disease in people with diabetes.

Commenting on the findings, Baker IDI’s Head of Diabetic Complications research Professor Jandeleit-Dahm said, “This is a very important break-through because cardiovascular disease is the leading cause of death for diabetic patients .”

Diabetic patients are susceptible to vascular complications such as atherosclerosis – a condition that involves thickening of the artery walls through a build-up of plaques. As a result, people with diabetes are at increased risk of stroke, myocardial infarction and death . The precise causes of this accelerated development of atherosclerosis have remained elusive but oxidative stress in response to high blood sugar appears to play a role.

This joint research initiative discovered that a gene known as NOX1 was associated with toxic amounts of oxygen radicals in the walls of blood vessels, which along with other inflammatory chemicals, leads to atherosclerotic plaque development.

Professor Schmidt said, “After zeroing-in on NOX1 as the main cause of oxidative stress in diabetes, we were able to examine the effects of suppressing this enzyme through gene manipulation as well as therapeutic drugs. What we discovered was that by inhibiting NOX1 in diabetic mice, we were able to significantly improve vascular health and prevent the development of plaque associated with atherosclerosis.”

The researchers are collaborating with a Swiss-based commercial bio-tech company called Genkyotex that has developed a NOX inhibitor known as GKT137831. Mice treated with the NOX inhibitor demonstrated a dramatic reduction in vessel damage, providing a new therapeutic approach to reduce oxidative stress in people with diabetes.

“Having narrowed our target, we can now focus on eliminating NOX1 with the aid of pharmacological therapies. Our ultimate goal is to translate these findings into a clinical treatment to reduce the burden of disease in diabetic patients,” said Professor Jandeleit-Dahm.

Following successful clinical safety studies, Phase II clinical studies with GKT137831 in patients with diabetic nephropathy are now in development.

The research is funded in part by a grant from JDRF, the world’s largest charitable funder of type 1 diabetes research.

For his research into oxidative stress prof Harald Schmidt received many grants, amongst others EU Marie Curie International Reintegration Grant (100 k€) and an Advanced Investigator Grant of the European Research Council (2,3 M€). He also chairs a research programme on this topic funded by the European Cooperation in Science and Technology (COST EU-ROS).